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[formula: see text] The use of the chiral quaternary ammonium salts 1a and 1b makes possible enantioselective Michael reactions which have been applied to the asymmetric syntheses of (S)-ornithine (2) and the chiral 2-cyclohexenone 6.
The structure of the active glyoxalase I inhibitor derived from the Streptomyces griseosporeus metabolite COTC 1 has been conclusively identified by means of total synthesis as 2c. Human glyoxalase I is competitively inhibited by 2c (K(i)() = 183 +/- 6 microM) but is not inhibited by 1 itself.
The stereocontrolled synthesis of (2S,4R,6R,8S,10S,1'R,1' 'R)-2(acetylhydroxymethyl)-4,10-dimethyl-8(isopropenylhydroxymethyl)-1,7-dioxaspiro[5,5]undecane (4a) and its C1' '-epimer (4b), the key mother spiroketals of the HIV-1 protease inhibitive didemnaketals from the ascidian Didemnum sp., has been carried out through multisteps from the natural (R)-(+)-pulegone, which involved the diastereoselective construction of four chiral carbon centers(C-2, C-6, C-8, and C-1') by intramolecular chiral induce.
[reaction in text] An approach to the potent immunosuppressant FR901483 is described. This route utilizes a tandem cationic aza-Cope rearrangement-Mannich cyclization to generate the core structure of this compound. In addition, this is the first demonstration of this tandem reaction passing through a bridgehead iminium ion.
[reaction: see text]We describe here an inherent problem in direct epoxidation of the endocyclic olefin in 2H-pyrans fused to 2-pyrones. Such difficulties led to the development of highly stereoselective trans- and cis-dihydroxylations of these olefinic systems in both 2H-pyrans and dihydropyridines fused to a 2-pyrones or a 2-cyclohexenone. Protocols for the removal of the activated allylic hydroxyl group are also reported.
A novel route to epoxysorbicillinol as well as dimers of sorbicillin is reported. The synthesis is-in principle-amenable to enantioselectivity. The key step is an oxidative dearomatization to produce a stable and highly malleable p-quinol intermediate, which undergoes a highly diastereoselective epoxidation.
[reaction: see text]. The synthesis of 2-phenyl-2,5-cyclohexadien-1-ones 1a-c and 2a-b from methyl 3-phenylbenzoate 4 and methyl 2-methoxy-5-phenylbenzoate 8 by the Birch reduction alkylation methodology is described. 1a-c and 2a-b undergo regiospecific photorearrangements at 300 nm to give tetrasubstituted phenols 14a-c and pentasubstituted phenols 18a-b, respectively. The type A photoproducts 17a-b resulting from irradiation of 2a-b at 366 nm have been isolated as approximately 1:1 diastereomer mixtures. When an optimized condition is applied, a single diastereomer of 17a is obtained.
The cyclohexenone segment 2 of scyphostatin (1), a potent inhibitor of neutral sphingomyelinase, was synthesized in an enantioselective manner starting from the bromo ether 5 and D-serinal derivative 3. The synthetic method features a coupling reaction of 5 with 3 to construct the asymmetric quaternary carbon center and a stereospecific epoxide ring formation as the key steps.
[reaction: see text] The A-ring precursor of 19-nor-1alpha,25-dihydroxyvitamin D(3) (1) and its (13)C- or (2)H-labeled derivative were efficiently synthesized from readily available, optically active 5-(tert-butyldimethylsilyloxy)-2-cyclohexenone (2) through a five-step reaction in 68% overall yield.
[reaction: see text] A surprising and synthetically useful counterion-dependent reversal of diastereoselectivity was found in 1,2-additions of hard carbon nucleophiles to C(6)-heterosubstituted cyclohexenones. In general, Grignard reagents added syn to the C(6)-substituent and Li reagents added anti, although some exceptions were found. Selectivities could be increased in some cases by appropriate choice of solvent and/or cosolvent.
[reaction: see text] A new methodology for the convergent synthesis of tetracyclic compounds was developed. Two new bicyclic Nazarov reagents of type II were synthesized, and their cycloaddition with 2-carbomethoxy-2-cyclohexenone I was studied. This cycloaddition afforded new interesting steroidal backbones.
[reaction: see text]. Mass spectral data are presented indicating that the antitumor agent 2-crotonyloxymethyl-2-cyclohexenone (COMC) is capable of alkylating oligonucleotides via a mechanism involving an electrophilic exocyclic enone intermediate. Under physiological conditions, the exocyclic enone is likely the glutathionylated 2-exomethylenecyclohexenone. This supports a recent hypothesis that the antitumor activity of COMC arises from alkylation of nucleic acids and/or proteins critical to cell function and not from competitive inhibition of glyoxalase I by an adduct of COMC and glutathione.
[reaction: see text] Data are presented indicating that the potent antitumor activity of 2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxy-2-cyclohexenone (COTC) and 2-crotonyloxymethyl-2-cyclohexenone (COMC) is not likely the result of glyoxalase I inhibition, as has long been assumed. An alternative hypothesis is presented, based on the finding that COMC is a substrate for human glutathionyl transferase, which produces a transient, highly electrophilic glutathionylated 2-exomethylenecyclohexanone that can covalently modify proteins and nucleic acids.
[reaction: see text] Syntheses of 6-epi- and 8-epi-otteliones, corresponding to earlier proposed structures of the biologically potent natural product ottelione A, have been accomplished from the readily available Diels-Alder adduct of cyclopentadiene and p-benzoquinone.
[reaction: see text] An approach to the highly functionalized tricyclic core of guanacastepene A has been developed using a rhodium(I)-catalyzed allenic Pauson-Khand reaction. This approach constitutes a conceptually novel strategy for the synthesis of this tricyclic framework, whereby the six-membered ring is formed intially followed by simultaneous formation of the five- and seven-membered rings.
[reaction: see text] The first enantioselective total synthesis of otteliones A and B, biologically important and structurally novel natural products, has been successfully achieved. This total synthesis fully confirms the absolute configuration of these natural products.
The reagent combination of catalytic amounts of copper hydride ligated by a nonracemic SEGPHOS ligand leads in situ to an extremely reactive species capable of effecting asymmetric hydrosilylations of conjugated cyclic enones in very high ees. An unprecedented substrate-to-ligand ratio as high as 275 000:1 for this transformation has been documented. [reaction: see text]
The first asymmetric total syntheses of ent-EI-1941-2 and epi-ent-EI-1941-2 have been accomplished, starting from a chiral epoxy iodoquinone 6, a key intermediate in our total syntheses of epoxyquinols A and B. A key step in the preparation of ent-EI-1941-2 is an intramolecular carboxypalladation via a 6-endo cyclization mode, followed by beta-hydride elimination, while carboxymercuration is a key step in the synthesis of epi-ent-EI-1941-2. [reaction: see text]